Fixed-dose bronchodilator combinations in chronic obstructive pulmonary disease: focus on indacaterol/ glycopyrronium

Chronic obstructive pulmonary disease (COPD) is a progressive disease involving persistent airflow limitation and a chronic inflammatory response of the airways. Recent clinical guidelines emphasize the importance of bronchodilators as the primary pharmacological treatment for COPD.

The aim this review was to examine the evolution of therapeutic approaches to COPD treatment, focusing particularly on the fixed-dose combination of indacaterol and glycopyrronium (FCIG).

Methods. Clinical trials evaluating the efficacy and safety of FCIG compared to monotherapy and other combination drugs were analyzed. The review discusses the synergistic mechanisms of long-acting beta-2 agonists (LABA) and long-acting anticholinergic drugs (LAMA), as well as the potential benefits of their simultaneous use. The review pays special attention to the effect of the fixeddose combination on lung functional parameters, exacerbation frequency, and patients’ quality of life, as well as its application in different clinical situations.

Results. The results of the analysis indicate significant clinical advantages of a fixed combination of FCIG in the treatment of patients with COPD of moderate to severe severity of bronchial obstruction. Results from an international, multicenter, randomized, open-label, comparative clinical trial evaluating the efficacy and safety of the generic combination of glycopyrronium bromide and indacaterol – drug Respihale® (PSK Pharma LLC, Russia) versus the branded drug Ultibro® Breezhaler® (Novartis Pharma AG, Switzerland) in patients with moderate COPD are also presented.

Conclusion. The fixed-dose indacaterol-glycopyrronium combination is a highly effective therapeutic option for patients with COPD, providing significant advantages over LAMA or LABA monotherapy, and in some clinical situations, compared with the LABA/ICS combination. To date, the first domestic dual bronchodilator containing glycopyrronium bromide and indacaterol has appeared on the market – the drug Respihale® (PSK Pharma LLC, Russia). The conducted clinical equivalence study confirmed non-inferiority and comparable safety of the reproduced drug in patients with moderate COPD.

1.

2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2025. Available at: https://goldcopd.org/2025-gold-report/

3. Ministry of Health of the Russian Federation. [Guidelines: Chronic obstructive pulmonary disease]. Available at: https://cr.minzdrav.gov.ru/view-cr/603_3?ysclid=mcvlfuacih806855093 (in Russian).

4. Barnes P.J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2016; 138 (1): 16–27. DOI: 10.1016/j.jaci.2016.05.011.

5. Montuschi P., Malerba M., Santini G., Miravitlles M. Pharmacological treatment of chronic obstructive pulmonary disease: from evidence-based medicine to phenotyping. Drug Discov. Today. 2014; 19 (12): 1928–1935. DOI: 10.1016/j.drudis.2014.08.004.

6. Cazzola M., Page C.P., Rogliani P., Matera M.G. β2-agonist therapy in lung disease. Am. J. Respir. Crit. Care Med. 2013; 187 (7): 690–696. DOI: 10.1164/rccm.201209-1739PP.

7. Vogelmeier C.F., Bateman E.D., Pallante J. et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir. Med. 2013; 1 (1): 51–60. DOI: 10.1016/S2213-2600(12)70052-8.

8. Beeh K.M., Westerman J., Kirsten A.M. et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2015; 32: 53–59. DOI: 10.1016/j.pupt.2015.04.002.

9. Tashkin D.P., Ferguson G.T. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir. Res. 2013; 14 (1): 49. DOI: 10.1186/1465-9921-14-49.

10. Suissa S., Dell'Aniello S., Ernst P. Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study. Lancet Respir. Med. 2018; 6 (11): 855–862. DOI: 10.1016/S2213-2600(18)30368-0.

11. Vogelmeier C.F., Bateman E.D., Pallante J. et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir. Med. 2013; 1 (1): 51–60. DOI: 10.1016/S2213-2600(12)70052-8.

12. Bateman E.D., Ferguson G.T., Barnes N. et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur. Respir. J. 2013; 42 (6): 1484–1494. DOI: 10.1183/09031936.00200212.

13. Wedzicha J.A., Decramer M., Ficker J.H. et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir. Med. 2013; 1 (3): 199–209. DOI: 10.1016/S2213-2600(13)70052-3.

14. Mahler D.A., Decramer M., D'Urzo A. et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur. Respir. J. 2014; 43 (6): 1599–1609. DOI: 10.1183/09031936.00124013.

15. Beeh K.M., Korn S., Beier J. et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir. Med. 2014; 108 (4): 584–592. DOI: 10.1016/j.rmed.2014.01.006.

16. Zhong N., Wang C., Zhou X. et al. LANTERN Investigators. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2015; 10: 1015–1026. DOI: 10.2147/COPD.S84436.

17. Kaplan A., Chapman K.R., Anees S.M. et al. Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study. Int. J. Chron. Obstruct. Pulmon. Dis. 2019; 14: 249–260. DOI: 10.2147/COPD.S185485.

18. Calzetta L., Rogliani P., Matera M.G., Cazzola M. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest. 2016; 149 (5): 1181–1196. DOI: 10.1016/j.chest.2016.02.646.

19. Van de Maele B., Fabbri L.M., Martin C. et al. Cardiovascular safety of QVA149, a combination of Indacaterol and NVA237, in COPD patients. COPD. 2010; 7 (6): 418–427. DOI: 10.3109/15412555.2010.528812.

20. Wedzicha J.A., Banerji D., Chapman K.R. et al. Investigators. indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N. Engl. J. Med. 2016; 374 (23): 2222–2234. DOI: 10.1056/NEJMoa1516385.

21. Oba Y., Sarva S.T., Dias S. Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. Thorax. 2016; 71 (1): 15–25. DOI: 10.1136/thoraxjnl-2014-206732.

22. Chapman K.R., Hurst J.R., Frent S.M. et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am. J. Respir. Crit. Care Med. 2018; 198 (3): 329–339. DOI: 10.1164/rccm.201803-0405OC.

23. Price D., West D., Brusselle G. et al. Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns. Int. J. Chron. Obstruct. Pulmon. Dis. 2014; 9: 889–904. DOI: 10.2147/COPD.S62750.

24. Vestbo J., Anderson J.A., Calverley P.M. et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009; 64 (11): 939–943. DOI: 10.1136/thx.2009.113662.

25. Miller S. Generic drugs: a treatment for high-cost health care. Mo Med. 2020; 117 (1): 12–13. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC7023936/

26. Zyryanov S.K., Aisanov Z.R. [Generic inhaled drugs: how to evaluate their properties?]. Pul'monologiya. 2012; (3): 115–119. Available at: https://journal.pulmonology.ru/pulm/article/view/92 (in Russian).

27. [International, open-label, randomized, comparative study of the efficacy and safety of Glycopyrronium bromide + Indacaterol, inhalation powder capsules, 50 + 110 μg (PSK Pharma LLC, Russia) and Ultibro® Breezhaler®, inhalation powder capsules, 50 + 110 μg (Novartis Pharma AG, Switzerland) in patients with COPD]. Protocol GLIND-3/20 of the clinical trial registry. 2020. Available at: https://grlsbase.ru/clinicaltrails/clintrail/11111 (in Russian).